Nondiamagnetic Agents in In Vivo 23Na and 1H2O MR

描述(申请人提供)：长期目标是探索和演示非抗磁性(这里是顺磁性)试剂效应在两个最强的组织核磁共振信号上的应用：1H2O和23Naaq(这里是1H2O)。提出的项目涉及日益重要的动态对比增强[团注跟踪(B-T)]MRI方法：在团注后记录对比剂[CR；单体Gd(III)螯合物]通道的高时空分辨率。B-T适应症可用于癌症、心肌缺血、中风、多发性硬化症和许多其他病理疾病。目前的授权期工作使我们处于两个主要MRI趋势的结合点：增加CR使用率和增加磁场强度[B0，以特斯拉(T)为单位]。我们发现，阈值检测浓度[CR]随着B0的增加而减小。定量的B-T药物动力学需要[CR]时间依赖关系，并且普遍假设[CR]依赖于测量的1H2O弛豫时间(T1)倒数。然而，我们表明，在临床BOS(&lt；3T)--恰好是在做出这一假设的地方--所需的CR水平足够高，以至于产生了重大错误。平衡跨细胞膜水交换动力学是这样的，即体系不处于线性关系所要求的快速交换极限(FXL)。一种新的分析，BOLERO(团注增强型松弛概述)，将交换动力学纳入松弛和药物动力学速率定律，可以处理在临床BO时确实获得的快速交换制度(FXR)，并且可以产生(和MAP)准确的绝对B-T参数测量：灌流、血管壁CR通透性和细胞外体积分数。然而，初步研究和波雷罗模拟预测了几个独特的高场实验，我们在这里建议用7T的大鼠进行实验。我们的具体目标有两大类：A.非脑ROI和B.脑ROI。对于A中的肌肉组织，我们将测试这样的假设，即我们可以检测到标准(0.1 mmol/kg)的CR剂量-1/10，之后系统实际上处于FXL中。这将允许第一次在体内评估CR弛豫度(与[CR]和T1-1相关的系数)，并将其与阴离子和中性CRS进行比较。在同一制剂中随后的标准剂量将产生测量平均细胞膜水渗透率和细胞大小以及细胞质水分数的新参数。我们还将在缺血肌中对它们进行比较。对于B，我们希望检测到轻微的CR血脑屏障渗透。虽然核医学CR示踪剂研究预测了这一点，但由于3T的检测阈值不够低，出现了与常规MRI相反的假说。我们还将准确地测量CRFirst-Pass超精细光头(取决于血药浓度)效应(而不是临床上的动态敏感性对比)，从而得出微血管动脉输入功能、脑血容量以及平均血管壁水渗透性和直径的绝对测量结果。我们将在胶质肉瘤、肿瘤生长和新型放射治疗缩小方面进行比较。它结合了数学、物理、化学、生物物理学、生物工程、生理学和生物医学的各个方面。

DESCRIPTION (provided by applicant): The long-term goal is to explore and demonstrate the applications of non-diamagnetic (here, paramagnetic) agent effects on the two strongest tissue NMR signals: 1H2O and 23Naaq (here, 1H2O). Projects proposed address the increasingly important dynamic- contrast-enhanced [bolus-tracking (B-T)] MRI approach: high spatiotemporal resolution recording of contrast reagent [CR; monomeric Gd(III) chelates] passage after bolus injection. B-T indications are found in cancer, myocardial ischemia, stroke, multiple sclerosis, and many other pathologies. Current grant period work has put us at the nexus of two major MRI trends: increasing CR usage, and increasing magnetic field strengths [B0, in Tesla (T)]. We have found that the threshold detection concentration, [CR], decreases with increasing B0. Quantitative B-T pharmacokinetics require the [CR] time-dependence, and a linear [CR] dependence on the measured 1H2O relaxation time (T1) reciprocal is universally assumed. However, we show that at clinical B0s (< 3 T) - precisely where this assumption is made - the CR level required is sufficiently high that significant errors are incurred. Equilibrium transcytolemmal water exchange kinetics are such that the system is not in the fast-exchange-limit (FXL,) required by the linear relationship. A new analysis, BOLERO (BOLus Enhanced Relaxation Overview), incorporating exchange kinetics into relaxation and pharmacokinetic rate laws, can handle the fast-exchange-regime (FXR) that does obtain at clinical B0s, and can yield (and map) accurate, absolute B-T parameters measuring: perfusion, vessel wall CR permeability, and extracellular volume fraction. However, preliminary studies and BOLERO simulations predict several unique high field experiments, which we propose here with rats at 7 T. Our specific aims have two major categories: A. Non-brain ROIs, and B. Brain ROIs. With muscIe tissues in A, we will test the hypothesis that we can detect a CR dose -1/10 the standard (0.1 mmol/kg), after which the system is actually in the FXL. This will allow the first in vivo evaluation of CR relaxivity (coefficient relating [CR] and T1-1), with comparison of anionic and neutral CRs. A subsequent standard dose in the same preparation will yield novel parameters measuring mean cytolemmal water permeability and cell size, and cytosolic water fraction. We will also compare these in ischemic muscle. With B, we expect to detect slight CR blood-brain-barrier permeation. Though predicted by nuclear medicine CR tracer studies, the contrary conventional MRI hypothesis arises because the detection threshold at < 3 T is not low enough. We will also accurately measure the CR first-pass hyperfine BALD (Blood Agent Level Dependent) effect (not the dynamic-susceptibility-contrast at clinical B0s), yielding absolute measures of the microvascular arterial input function, the cerebral blood volume, and the mean vessel wall water permeability and diameter. We will compare these in gliosarcoma tumor growth and novel radiotherapeutic shrinking. This combines aspects of mathematics, physics, chemistry, biophysics, bioengineering, physiology, and biomedicine.